Abstract Localized prostate cancer is often categorized as either indolent or aggressive based largely on clinical and pathological features. Despite our understanding of genetic alterations that are associated with different stages of prostate cancer (PCa), there is no clear molecular classification system, which can predict the risk for developing aggressive PCa. As a result, it is currently difficult to discriminate the aggressive and indolent PCa in their early stages, and develop appropriate therapy for the patients with aggressive cancer. Surgery, radiation and less often androgen deprivation therapies are the available treatment options for localized tumor, although cancers of 30-35% of patients recur and some of them evolve into metastatic disease. There are very limited treatment options for advanced stage PCa. It is therefore important to identify the molecular mediators that promote the advancement of PCa. A comprehensive knowledge on the function of these mediators will not only help us to determine the molecular factors that can distinguish the aggressive and indolent PCa but also to establish effective treatment modalities for those patients who are at high risk to develop metastatic cancer. Our preliminary results indicated that Neuropilin-2 (NRP2) could be a mediator of aggressive PCa by regulating the global transcription of genes required for cancer promotion. Mechanistically, NRP2 can translocate from ER to nuclear membrane through retrograde transport and stabilize the transcription machineries necessary for the expression of cancer promoting genes. Based on these novel observations, we hypothesized that nuclear NRP2 is critical for the transcription of genes required for the advancement of PCa. Hence, NRP2 is not only a predictor for aggressive PCa but also a target for effective treatment strategy. Two specific aims have been proposed. In aim 1, we will study the underlying mechanisms of how nuclear membrane-bound NRP2 interacts with the transcription factors in PCa cells and facilitates their activity. We will also determine using a cohort of human PCa tissues whether nuclear NRP2 can be a prognostic factor, which can discriminate between indolent and aggressive PCa. Aim 2 will focus on the molecular mechanism of how NRP2 migrates to nuclear membrane and determine whether inhibition of this translocation can block the prostate tumor growth. Altogether, our proposal will determine how nuclear NRP2 promotes PCa and thus can be an effective predictor for aggressive PCa. Moreover, it will identify whether targeting NRP2 axis such as blocking its nuclear transport is an effective therapeutic approach to treat aggressive PCa.